tbuckley/cabot-search huggingface dataset:
Biomarkers for response to immunotherapy in triple-negative breast cancer: Differences between survival and pCR biomarkers.
Authors: Carsten Denkert, Andreas Schneeweiss, Julia Rey, Thomas Karn, Michael Braun, Jens Bodo Huober, Hans-Peter Sinn, Dirk Michael Zahm, Claus Hanusch, Frederik Marmé, Jenny Furlanetto, Joerg Thomalla, Jens U. Blohmer, Marion van Mackelenbergh, Peter Staib, Christian Jackisch, Peter A. Fasching, Bruno Valentin Sinn, Michael Untch, Sibylle Loibl
Journal: Journal of Clinical Oncology (2022)

583 Background: Immunotherapy is entering clinical practice as a promising new neoadjuvant therapeutic approach in triple-negative breast cancer, and it is important to identify biomarkers to focus this therapy on those patients that have the highest benefit. Interestingly, an improved survival outcome is observed in pCR and non-pCR patients, which raises the hypothesis that biomarkers might also be different for pCR prediction as well as prognosis. In this study, we investigated this hypothesis in the neoadjuvant GeparNuevo trial. Methods: A total of 174 patients were randomized to receive neoadjuvant chemotherapy with durvalumab vs. placebo. HTG EdgeSeq mRNA analysis was performed for a total of 2549 genes in 162 pretherapeutic core biopsies. In addition, tumor-infiltrating lymphocytes (stromal and intratumoural) as well as PD-L1 protein expression was evaluated by IHC. We systematically compared the distant disease-free survival (DDFS) of 5 predefined gene signatures (including the GeparSixto immune signature) as well as 12 single mRNA markers identified in previous projects between treatment arms using univariate Cox proportional-hazard regression analyses. In addition, exploratory biomarker analyses were performed. Results: The PSIP1 gene expression (per 1 unit hazard ratio [HR]: 0.58 95%CI 0.41-0.83; p=0.002), TAP1 (per 1 unit HR: 0.68 95%CI 0.48-0.95; p=0.025) as well as stromal TILs (sTILs) (per 10% HR: 0.73 95%CI 0.56-0.95; p=0.019) were significant for improved DDFS in the complete cohort. In the placebo arm PSIP1 (HR 0.50 95%CI 0.29-0.87; p=0.014) as well as sTILs (HR 0.73 95%CI 0.53-0.99; p=0.044) were significant for improved DDFS. In the durvalumab arm, the gene expression of PSIP1 (HR 0.54 95%CI 0.31-0.94; p=0.029), PD-L1/CD274 (per 1 unit HR: 0.41 95%CI 0.21-0.77; p=0.006), CD38 (per 1 unit: HR 0.52 95%CI 0.29-0.92; p=0.026) as well as the GeparSixto immune signature (per 1 unit HR: 0.51 95%CI 0.27-0.97; p=0.041) were significant for improved DDFS, with a positive test for interaction with treatment arm for PD-L1/CD274 (interaction p=0.020). Additional analyses, including multivariate Cox regressions for DDFS as well as systematic comparisons for biomarkers for DDFS and for pCR, will be presented. Conclusions: Our analysis suggests that biomarkers for immune response are linked to improved survival with neoadjuvant durvalumab therapy and that in this setting, survival biomarkers are not identical to pCR biomarkers. The results are a basis for a further dissection of the contribution of pCR to survival effects of immunotherapy.
Immune responses after omicron infection in triple-vaccinated health-care workers with and without previous SARS-CoV-2 infection
Authors: Kim Blom, Ulrika Marking, Sebastian Havervall, Nina Greilert Norin, Max Gordon, Marina García, Teghesti Tecleab, Wanda Christ, Mattias Forsell, Mia Phillipson, Peter Nilsson, Sara Mangsbo, Sophia Hober, Mikael Åberg, Jonas Klingström, Charlotte Thålin
Journal: The Lancet Infectious Diseases (2022)
FAT4 mutation as a potential predictive biomarker for immunotherapy combined with anti-angiogenic therapy in MSS metastatic colorectal cancer.
Authors: Mifen Chen, Qi Zhang, Hui Chen, Zhenghang Wang, Ting Xu, Changsong QI, Shiqing Chen, Xiaochen Zhao, Yuezong Bai, Zhi Peng, Xicheng Wang, Xiaotian Zhang, Jifang Gong, Lin Shen, Jian Li
Journal: Journal of Clinical Oncology (2022)

e15504 Background: Microsatellite stable (MSS) metastatic colorectal cancer (CRC) lacks effective treatments and has a poor prognosis. The aim of this study was to identify patients who could benefit from immunotherapy combined with anti-angiogenic therapy. Exploration of predictive biomarkers could help to maximize the clinical benefits. Methods: In total, FFPE tissues samples before immunotherapy combined with anti-angiogenic therapy of 21 patients were successfully tested for tumor microenvironments (TMEs) by multiple immunofluorescence, of which 11 of them were successfully detected by 733-gene NGS panel in a CLIA-certified laboratory. The correlation between gene variations and clinical durable benefit (DCB: PR, or SD≥6 months), PFS and TMEs were analyzed by Fisher's test, K-M survival curve analysis and Mann Whitney analysis respectively. Results: Significant difference was detected between FAT4 mutation (FAT4-MUT) and FAT4 wildtype (FAT4-WT) regarding DCB (100%, 4/4 vs 17%, 1/7, P = 0.0152) and progress-free survival (median PFS, 13.8 months vs 2.8 months, LogRank P = 0.003). There was no significant difference in TMB level between DCB and NDB (SD＜6 months, or PD) groups (12 mut/Mb vs 6 mut/Mb, P = 0.0823) or between FAT4-MUT and FAT4-WT (11 mut/Mb vs 6 mut/Mb, P = 0.3697). TMEs analyses revealed that the CD3+CD4+ T cell proportion was tended to be higher in FAT4-MUT (0.7% vs 0.3%, P = 0.054). Further TIMER2.0 data showed FAT4-MUT was significantly associated with higher Immune infiltration of four immune cells, including CD4+ T cell in both colon and rectal adenocarcinoma, CD8+ central memory T cell, B cell, and Macrophage in colon adenocarcinoma. Conclusions: Our findings indicated that FAT4 mutation serves as a potential novel biomarker correlated with a better response to immunotherapy combined with anti-angiogenic therapy in MSS metastatic CRC, which may be related to the activation of CD4 T cell infiltration. However, these need to be validated by further cohort expansion.
A systematic review of the literature on gastrointestinal tract amyloidomas: Presentation, management and outcomes.
Authors: Mariuxi Alexandra Viteri Malone, Anahat Kaur, Abhishek Kumar
Journal: Journal of Clinical Oncology (2022)

e16220 Background: Gastrointestinal tract amyloidomas are uncommon malignancies, and little is known regarding this entity. AL amyloidosis and Amyloidomas mostly occurs in association to plasma cell dyscrasias such as multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS), and Waldenstrom’s macroglobulinemia (WM), although it has been also described in the absence of plasma cell dyscrasias. In general, plasma cell dyscrasias and systemic amyloidosis either AL or AA are typically treated with systemic therapy followed by Hematopoietic Stem Cell Transplant (HSCT) if patient is eligible. Nowadays, there are several systemic approaches that may or may not include autologous stem cell transplant. 56 On the contrary, localized amyloidomas have been mostly managed surgically and for the most part local amyloidomas are considered to have excellent prognosis. To this date there is no standard of care to guide clinicians in the management of local gastrointestinal amyloidomas. To the best of our knowledge this is the largest systematic review of gastrointestinal amyloidomas. The objective of this study was to evaluate the characteristics, treatments available, outcomes and surveillance these patients. Methods: We conducted a systematic review of cases reported in the literature from 1962-2021 that included a total of 62 cases reported in the literature. Patients with Gastrointestinal Amyloidomas reported in English literature were included in the analysis. We described and summarized the patient’s characteristics, treatments, clinical presentations, outcomes, and surveillance. Results: The systematic review of reported clinical cases included 62 patients. In these patients, the most common site of amyloid deposition was the stomach (45%). The median age of diagnosis is 64.4 years old, has a 2:1 prevalence among males (63%) to females (37%), abdominal pain is the most common type of presentation (41%) although patients could also be asymptomatic. There is a high curative rate (100%) with resection alone. Among patients treated with a type of systemic therapy, an 80% achieved a complete response. The minority of cases reported a type of surveillance post treatment and among those, the 62% pursued serial clinical evaluations alone. Conclusions: To our knowledge, this is the first and largest systematic review of the literature in Gastrointestinal Tract Amyloidomas. This is more common among males, and seems to have an excellent curative rate (100%) with surgery alone. Systemic therapy is an option for those with non-resectable amyloidomas. Serial clinical evaluations should be part of the standard surveillance care in these patients.
Adverse health outcomes (AHO) in testis cancer survivors (TCS) following high-dose chemotherapy (HDCT) and autologous stem cell transplant.
Authors: Meagan Elizabeth Miller, Ryan Ashkar, Sandra K. Althouse, Nasser H. Hanna, Rafat Abonour, Lois B. Travis, Lawrence H. Einhorn, Nabil Adra, Mohammad Issam Abu Zaid
Journal: Journal of Clinical Oncology (2022)

12083 Background: Patients with relapsed/refractory germ cell tumors are often cured with tandem platinum-based HDCT followed by autologous stem cell transplant in the ≥2nd line treatment setting. A comprehensive assessment of long-term AHO (adverse health outcomes) in TCS cured with HDCT has not been previously described. Methods: Testis cancer survivors (TCS) at least 1 year after HDCT and treated at Indiana University were eligible. TCS were asked to complete a comprehensive, well validated survey regarding 19 different AHO. TCS demographics, disease characteristics, treatment received, and AHO were collected. Results: From 2/2021-1/2022, 118 eligible TCS were invited. 70 TCS completed the survey (59.3% completion rate). TCS received HDCT followed by autologous stem cell transplant in the 2 nd (91.4%), 3 rd (7.1%) or 4 th line (1.4%) setting. At the time of survey completion, 93% of respondents were at least two years from HDCT (range 1.6-16.2 y) with a median age of 42 y (range 24.8-66.6 y). Median age at the time of original germ cell tumor diagnosis was 32 y (range 17.4-56.8 y). TCS reported a median of 3 AHO with 37% of participants reporting 5 or more AHO. 90% of participants reported tinnitus, 91% experienced hearing impairment, and 52% required the use of hearing aids. Additionally, 46% TCS noted peripheral neuropathy and 26% reported problems with balance/vertigo/dizziness. Prevalence of kidney disease was 10%, and 24% TCS experienced erectile dysfunction. In regards to physical activity, 47% of participants were not participating in vigorous physical activity (defined as &gt; 6 mets/week). 16% TCS reported use of medications to treat anxiety and/or depression, and 19% required testosterone replacement therapy. The prevalence of hypertension, coronary artery disease, Raynaud phenomenon, hypercholesterolemia, diabetes, and thyroid disease were 13%, 1%, 17%, 12%, 4%, and 6% respectively. Conclusions: Despite the high cure rate of HDCT, TCS report a substantial burden of morbidity with the majority experiencing ototoxicity, and with half of the TCS requiring hearing aids. Special attention to these AHO and efforts to develop ototoxicity prevention approaches are urgently needed for this patient population.
MODL-22. Establishment of a novel system to specifically trace and ablate quiescent/slow cycling cells in high-grade glioma
Authors: Francesco Antonica, Lucia Santomaso, Davide Pernici, Linda Petrucci, Giuseppe Aiello, Alessandro Cutarelli, Luciano Conti, Alessandro Romanel, Evelina Miele, Toma Tebaldi, Luca Tiberi
Journal: Neuro-Oncology (2022)

Abstract Pediatric and adult high-grade gliomas are the most common malignant brain tumors, with poor prognosis due to recurrence and tumor infiltration after surgical removal and chemotherapy. Quiescent/slow cycling stem cells have been proposed to be one of the main players of tumor relapse but their involvement in in the infiltration remain unclear. Despite they have been described in mouse models or after transcriptional profiling of human tumor samples, their direct visualization, targeting and ablation remains a challenge. Here, we identified a population of malignant cells expressing Prominin-1 in a non-proliferating state in pediatric high-grade glioma patients. We next used a fluorescent cell cycle sensor to visualize quiescence tumor cells in mouse brain cancer and human cancer organoids. In particular, we characterized them within the tumor revealing the invasiveness capacity of slow cycling tumor cells. Furthermore, we generated a new system to specifically trace and ablate such cells. Indeed, lineage tracing experiments allowed to trace quiescent Prom1 progeny in the tumors after temozolomide treatment. In addition, the selective ablation of quiescent Prom1+ cells in mouse brain cancer reduced tumor infiltration and improved survival. Furthermore, time-lapse experiments showed that slow cycling cells are also able to infiltrate co-cultured human brain cancer organoids. Finally, using our new cancer organoid- and GBM spheroids-based models we identified a drug acting on quiescent cells leading to a reduction in cell invasion. Overall, our data show that quiescence/slow cycling cells are key driver of tumor invasiveness, the major malignant feature of high-grade brain cancer.
Attitudes of physicians and patients toward the timing of adjuvant treatment in colon cancer.
Authors: Mehraneh D. Jafari, Julianna Brouwer, Andrea Mesiti, Chelsea McKinney, Lari B. Wenzel, Alessio Pigazzi, Jason A. Zell
Journal: Journal of Clinical Oncology (2022)

e15596 Background: We have previously shown in a Phase I trial that administration of immediate adjuvant chemotherapy (IAC) at the time of surgical resection and immediately postoperatively is safe and feasible in colon cancer (CC) patients. IAC avoids delays in adjuvant treatment and has the potential to improve survival and quality of life. However, two fundamental questions must be answered: will patients be willing to accept the possibility of more severe side effects in exchange for earlier treatment (Tx) completion and theoretically better survival? And will physicians depart from established CC treatment practices?. Methods: A web-based survey was administered to newly diagnosed CC patients (within 1 year of surgery) and survivors (&gt; 1 year post op). A similar web-based survey was administered to surgeons and medical oncologists in academic and community settings across the country. Surveys assessed patients’ and providers’ treatment preferences, attitudes towards care, and perceived barriers to IAC. Descriptive statistics were conducted including chi-square tests to compare differences between patients’ and providers’ responses. Results: Responses were collected from 35 patients and 40 providers. Patient respondents were 48% survivors and 52% newly diagnosed CC patients. Among the providers, 60% of the medical oncologists and 75% of the surgeons worked at academic medical centers. Compared to providers, patients were more willing to: 1) proceed with IAC to finish treatment earlier thereby improving quality of life (p = 0.002); 2) proceed with IAC to finish treatment earlier, despite potential side effects (p &lt; 0.001); and 3) proceed with a single dose of intraoperative chemotherapy that, based on final pathologic stage, may not be needed (p = 0.002). Patients were also more likely than providers to indicate that there are no barriers to collaborative care (p = 0.001) while providers were more likely to cite that collaborative care is time consuming (p = 0.001), comes with scheduling challenges (p = 0.001), and that physicians are not readily available to participate in it (p = 0.003). Conclusions: We observed a disconnect between what providers and patients value in the perioperative and adjuvant colon cancer treatment course. Colon cancer patients are willing to accept intraoperative chemotherapy and early adjuvant chemotherapy via this novel multidisciplinary approach even if this treatment were associated with additional side effects, and without promise of a survival benefit.[Table: see text]
Sutureless purely off-clamp robotic partial nephrectomy: Technique and perioperative outcomes
Authors: L. Misuraca, A. Brassetti, U. Anceschi, G. Tuderti, R. Mastroianni, M. Ferriero, A.M. Bove, S. Guaglianone, M. Gallucci, G. Simone
Journal: European Urology (2022)
Violent incidents at GP surgeries double in five years,<i>BMJ</i>investigation finds
Authors: Gareth Iacobucci
Journal: BMJ (2022)

The number of violent incidents at UK general practices recorded by police forces has almost doubled in the past five years, an investigation by The BMJ has found. Crime figures obtained from police forces around the UK show that violent incidents at GP surgeries and health centres have increased every year since 2017. Worryingly, the figures also show a near doubling of assaults that cause physical harm. The rise in violent incidents and abuse aimed at GPs and their staff is causing some to leave their jobs, GPs have warned (boxes 1-3). "We have to try to address this because it leads to burnout of our staff, demoralisation, and staff leaving the service altogether," said Richard Vautrey, a GP in Leeds and former chair of the BMA's General Practitioners Committee. Box 1 ### "He said was going to hurt somebody" Alan Stout, a GP in east Belfast and chair of the Northern Ireland General Practitioners Committee, told The BMJ how a recent incident of violence at the hands of a patient in March had affected GPs and staff: "It began with a phone consultation—a patient was looking for additional medication. He got progressively more aggressive throughout the course of the conversation, and it culminated in him saying that he was coming down to the practice there and then and he was going to hurt somebody. So we locked the front door. The staff were in the reception and office area; there was only one doctor on [duty] at the time, and he was in his consulting room. "The individual then appeared, kicked the locked front door down and stormed in, and then started attacking the door and the window to the reception where the reception staff were. At this point the doctor then had to lock themselves in their room. The police were contacted and subsequently arrived, and he was … RETURN TO TEXT
Author Correction: Mapping microglia states in the human brain through the integration of high-dimensional techniques
Authors: Roman Sankowski, Chotima Böttcher, Takahiro Masuda, Laufey Geirsdottir, None Sagar, Elena Sindram, Tamara Seredenina, Andreas Muhs, Christian Scheiwe, Mukesch Johannes Shah, Dieter Henrik Heiland, Oliver Schnell, Dominic Grün, Josef Priller, Marco Prinz
Journal: Nature Neuroscience (2022)
Ischemic postconditioning activates cardiac MMP-2 and decreases biglycan level as well as miR-34a-5p and miR-195-5p expression in early reperfusion in a porcine infarction model
Authors: T Szabados, K Gomori, P Ferdinandy, M Gyongyosi, A Gorbe, P Bencsik
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Kooperatív Doktori Program Doktori Hallgatói Ösztöndíj (KDP-2020) Hungarian Scientific Research Fund-OTKA-138223 Background Matrix metalloproteinase-2 (MMP-2) has been shown to be activated during myocardial ischemia-reperfusion (IR) injury leading to degradation of cardiac contractile proteins. In previous investigation, ischemic postconditioning (IPoC) failed to decrease myocardial necrosis in porcine model of acute myocardial infarction (AMI). However, IPoC significantly reduced the severity of myocardial microvascular obstruction (MVO) compared to ischemic control. Therefore, our aim was to reveal if two major extracellular players of cardiac pathophysiology, MMP-2 and biglycan (BGN) are involved in the MVO reducing effect of IPoC in a porcine AMI model. Methods AMI was induced in female domestic pigs (25-35 kg) with balloon catheter occlusion of the left descending coronary artery for 90 min in ischemic control group. IPoC group underwent 6×30 s I/R after 90-min occlusion. At the end of the 3-hour or 3-day reperfusion, infarcted left ventricular tissue samples were taken to determine MMP-2 activity and BGN levels as well as cardiac microRNA (miRNA) expression. Results Cardiac MMP-2 activity showed significant increase in IPoC group as compared to ischemic control after 3h reperfusion but after 3d reperfusion no significant change was observed between the two groups. Cardiac BGN level in IPoC was significantly decreased as compared to ischemic control after 3h reperfusion, which difference was also abolished after 3d reperfusion due to the decrease of BGN level of ischemic control group. Ischemic postconditioning altered the expression of three miRNAs: miR-34a-5p, and miR-195-5p were downregulated, and miR-15b-5p was upregulated as compared to ischemic control. Conclusions IPoC decreased MVO and BGN level and increased MMP-2 activity in the infarcted left ventricle during early reperfusion, and altered the expression on 3 cardiac miRNAs. Further increase was found in MMP activities after 3 days in both groups, which affected BGN level only in ischemic control group. Altered expression of miRNAs and early decrease in cardiac BGN level may contribute to the beneficial effect of IPoC on MVO.